Aminoalkyl esters of n, n-diarylanthranilic acids and salts thereof



Patented May 13, 1952 AMINOALKYL ESTERS OF N,N-DIARYLAN- THRANILIC ACIDS AND SALTS THEREOF Carl Peter Krimmel, .Evanston, Ill., assignor to G. D. Searle & Co., Chicago, Ill.,a corporation of Illinois No Drawing. Application April 20, 1949, Serial No. 88,699

15 Claims. 1 This application relates to aminoalkyl esters of N,N-diarylaminobenzoic acids, to the salts thereof, and to methods of preparing such compounds. More particularly this invention relates to basic esters of the following general formula Ar-N wherein Ar and Ar are aryl radicals, R is an alkylene radical, and Bis an aliphatic-type amino radical.

In the foregoing structural formula Ar and Ar may be the same or difierent aryl radicals and are preferably aryl radicals of the benzene series. Among such radicals are phenyl, anisyl, phenetyl, tolyl, xylyl, ethylphenyl, naphthyl, xenyl, and related radicals. R represents a bivalent aliphatic hydrocarbon radical containing 2 to 5 carbon atoms. Preferably R representsa lower alkylene radical, which may be straight or branch-chained, including ethylene, propylene, 1,2-,, 2,3- and 1,3-butylene, andthe amylene radicals, and polymethylen radicals containingrfrom 2 to 5 carbon atoms. The amino radical Brepresents aliphatic amino groups and cyclic amino groups which are aliphatic in character. Among such amino groups are the mono-(lower alkyl),

amino groups and di- (lower alkyl) amino groups wherein the alkyl radicals contain 1 to 5 carbon 1 atoms. hydroxyalkyland dihydroxyalkylamino groups are within the scope of this invention. Cyclic amino groups such as piperidino, pyrrolidino, morpholino, thiamorpholino, piperazino, lupetidino, and related amino radicals derived from aliphatic-type heterocyclic amines having disassociation constants in the range of 10- tom are also within the purview of this invention.

The compounds of this invention are preferably prepared by reacting anacid of the general structural formula e coon Ar-N are generally carried out in inert organic solvents having boiling points in the range of 50-:150 C.

Other aliphatic amino groups such as readily soluble in water.

Among such solvents are ethanol, propanol, isopropanol, butanol, acetone, methyl ethyl ketone, benzene, toluene, xylene, cyclohexane, and hydrocarbon fractions boiling in the range oi; -150 0., as Wellas high boiling ethers such'as dibutyl ether. The reactions are generally carrie'd'out by mixing equivalent quantities of the .acid and amino halide and refluxing the mixture, in an. inert solvent for several hours. Reasonable excesses of either reagent are not deleterious. Often slight excesses (25%) of the basic halide are used. In certain instances the hydrohalide of the basic ester is insoluble in the reaction medium and crystallizes out upon cooling. These crystalline salts may be removed by filtration and purified by washing and/or recrystallization. In cases where the salt of the basic ester is soluble in the organic medium, the esters may be isolated by evaporation of the solvent followed by extraction of the organic base from an aqueous alkaline solution. The bases in general can be distilled under reduced pressure. They are usually light colored viscous oils, which are readily soluble in aqueous acids and in organic solvents. The basic esters form crystalline salts with strong acids including hydrochloric, hydrobromic, sulfuric, phosphoric, sulfamic, tartaric, citric, malic, maleic, lactic, oxa1ic,.cinnamic, acetic, 'benzoic, and similar acids. Quaternary ammonium salts can be'prepared by reacting the basic ester with an aliphatic or aromatic-aliphatic ester of a strong acid, generallyin an inert solvent. These salts are often crystalline powders which are Among the esters of strong acids which can be used are methyl chloride, methyl iodide, ethyl bromide, benzyl chloride, phenethyl bromide, ethylene bromohydrin, dimethyl sulfate, methyl p toluenesulfonate, ethyl benzenesulfonate, diethyl sulfate, propylene bromohydrin, monochlorohydrin and related esters ofstrong acids.

The acids which are used as starting materials in ny ro esses can be prepared by reacting an aminobenzoicacid withan aryl halide, preferably an aryl iodide, in the presence of copper powder and alkali inan inert high-boiling solvent at temperatures-in the range of ZOO-250 C. The acids may be obtained in pure form by removal of volatile materials by steam distillation followed by acidification of the aqueous residue.

:The substances of my invention are useful as chemical intermediates in the synthesis of dyestufl's and drugs. They are also of value as pharmaceutical agents. Certain of them have diuretic .and coronary activity, while others have spasmolytic and antihistaminic action. For the latter purposes; a preferred form of the compounds of this invention is as water-soluble salts, particularly as salts of mineral acids.

My invention is disclosed in further detail by the following examples which are provided solely for the purpose of illustrating the invention and which are intended in no way to be construed as limiting it in spirit or in scope. Relative amounts of materials are given in parts by weight.

Example 1 333 parts of N-phenyl-N-p-phenetylanthranilic acid are dissolved in 4000 parts of dry, boiling isopropanol. Then 136 parts of ,B-diethylaminoethyl chloride are added and the solution is refluxed for hours. The solvent is stripped off under vacuum. The residue is dissolved in water and the solution is washed with ether. The solution is made alkaline and extracted with ether. The ether extract is dried and evaporated, and the residue of fi-diethylaminoethyl N-phenyl-N-p-phenetylanthranilate is distilled under reduced pressure; boiling point 230-240 C. at 0.8 mm. pressure.

12 parts of the foregoing ester are dissolved in 650 parts of dry ether and treated with an equivalent o fanhydrous hydrogen chloride in dry isopropanol. The precipitate of fi-diethylaminoethyl N-phenyl-N-p-phenetylanthranilate hydrochloride is recrystallized from methyl ethyl ketone; It melts at 173-175" C. with sintering from 160 C.

- Example 2 By the method of Example 1, 333 parts of N- phenyl-N-p-phenetylanthranilic acid are reacted in 4000 parts of dry, boiling isopropanol with 108 parts of fi-dimethylaminoethyl chloride over a period of 6 hours. The solvent is removed and the residue of fi-dimethylaminoethyl N-phenyl- N-p-phenetylanthranilate hydrochloride is taken up in water. The aqueous solution is washed with ether to remove organic material and then made alkaline. The basic ester is removed by extraction with ether. After drying and removal of ether, fi-dimethylaminoethyl N-phenyl-N-pphenetylanthranilate is purified by distillation in vacuo.

Example 4 185 parts of N,N-diphenylanthranilic acid are suspended in 2500 parts of dry isopropanol. Then 105 parts of 'y-diethylaminopropyl chloride are added; The mixture is refluxed and agitated for 5 hours, during which time the acid dissolves. The hot solution is filtered and evaporated under vacuum. The residue of *y-diethyh aminopropyl N,N-'diphenylanthranilate hydrochloride is dissolved in water and washed with ether to remove water-insoluble organic materlals. The aqueous solution is made alkaline with caustic soda solution and extracted with ether. The ether extract is dried and stripped of solvent. The residue of v-diethylaminopropyl N,N-diphenyla nthranilate is purified by distillation under reduced pressure.

4 Ea'ample 5 400 parts of N-phenyl-N-p-tolylanthranillc acid and 177 parts of B-diethylaminoethyl chloride are reacted in 4000 parts of anhydrous isopropanol by the method of Example 1. The basic ester is isolated by the method of Example 1 and distills at 230240 C. at 1.5 mm. pressure. It forms a crystalline hydrochloride melting at 188190 C.

Example 6 390 parts of N,N-diphenylanthranilic acid are heated with 268 parts of fi-di-n-butylaminoethyl chloride in 5000 parts of boiling isopropanol for 5 hours. The solvent is removed by evaporation and the residual salt is treated with dilute aqueous alkali. The resulting mixture is extracted thoroughly with ether and the ether extract is dried, filtered and evaporated. There is thus obtained a light-colored oily residue of fi-di-nb'utylaminoethyl N,N-diphenylanthranilate.

Example 7 290 parts of N,N-diphenylanthranilic acid are reacted with 110 parts of S-dimethylaminoethyl chloride in 320 parts of anhydrous isopropanol according to the method of Example 1. The organic base is isolated as in Example 1. It is dissolved in dry ether and treated with an equivalent of anhydrous hydrogen chloride in isopropyl alcohol. The crystalline hydrochloride is collected on a filter, washed, and dried. After recrystallization from acetone it melts at 202-204 0.

Example 8 N-phenyl-N-o-tolylanthranilic acid, there is pro- N -phenyl-N-o-tolduced fidiethylaminoethyl ylanthranilate. This compound distils at 210-215 C. at 0.5 mm. pressure. It forms a crystalline hydrochloride which melts at 191-:193

C. after recrystallization from methyl ethyl ketone. l Example 10 By the method of Example 1, 220 parts of N- phenyl-N-2A-xylylanthranilic acid are reacted for 5 hours with parts of S-diethylaminoethyl chloride in 4000' parts of dry refluxing isopropanol. The product, B-diethylaminoethyl N- phenyl-N-2,4-xylylanthranilate, is isolated as above. It distils at 219-223 C. at 1.0 mm. pressure. It forms a crystalline hydrochloride which melts at 191-193" C.

Example 11 light-colored oil which is soluble in organic solvents.

Example 12 388 parts of N,N-diphenylanthranilic acid and 148 parts of B-piperidinoethyl chloride are refluxedtogether in 4000 partsof dry isopropanol according to the procedure of Example 1. B- Piperidinoethyl N,N-diphenylanthrariilate is isolated by the method of Example 1. This oily base can be purified by distillation under high vacuum.

Example 13 388 parts of N,N-diphenylanthranilic acid and 149 parts of B-morpholinoethyl chloride are reacted in 4000 parts of anhydrous isopropanol according to the general method of Example 1. The B-inorpholinoethyl N ,N-diphenylanthranilate hydrochloride which is left after removal of the solvent crystallizes on standing. This material is washed with alcohol and recrystallized from nitrobenzene. It melts at 246-250 C. (with softening from 235 C.)

Exampl 14 Example 15 To a suspension of 165 parts of N,N-di(ptolyl) -anthranilic acid in 3000 parts of anhydrous methyl ethyl ketone are added 72 parts or fl-diethylaminoethyl chloride. The mixture is agitated and refluxed for 6 hours. It is filtered hot with activated charcoal and evaporated under vacuum. The residue is treated with dilute caustic soda and extracted with ether. The ether solution is dried and evaporated. There is thus produced an oily light-colored residue of fi-diethylaminoethyl N,N-di(p-tolyl) anthranilate.

Example 16 A mixture of 69 parts N-phenylanthranilic acid, 279 parts of o-iodotoluene, 20 parts of copper powder, 40 parts of anhydrous potassium carbonate and 240 parts of nitrobenzene is refluxed for 6 hours. The mixture is then distilled with steam and the aqueous residue is filtered, chilled and made acidic. The pale yellow precipitate of N-phenyl-N-o-tolylanthranilic acid is collected on a filter and washed with water. It is recrystallized from dilute methanol and. from glacial acetic acid; M. P. 173-l76 C. with sintering from 171 C.

N-phenyl-N-m-tolylanthranilic acid is prepared similarly using m-iodotoluene. It melts at 145-149 C. after recrystallization from dilute ethanol.

N phenyl N 2,4 xylylanthranilic acid is prepared by the foregoing method, using 29'? parts of 4-iod0-1,3-dimethylbenzene in lieu of 279 parts of iodotoluene. It melts at l85-188 C. after recrystallization from alcohol and glacial acetic acid.

N-phenyl-N-p-phenetylanthranilic acid is made by the same procedure, using 317 parts of p-iodophenetole in place of 279 parts of iodotoluene. It meltsat -138 C. after recrystallization from ethanol.

N-phenyl=N-p tolylanthranilic acid is prepared by the foregoing method from 69 parts 01' N phenylanthranilic acid and 279 parts of piodotoluene. After recrystallization from "alcohol this acid melts at 174-176 I claim: i 1. A memberoi thegroup consisting of a basic ester of the formula Y Y i andsalts thereof, wherein X, X, Y and Yf. are members of the group consisting'otwhydrogen, lower alkyl and lower allroxyl radicals, R is a lower alkaline radical, and B is an amino radical selected from the group consisting of di(lower alkyl) amino, N-piperidino, N-morpholino and N-pyrrolidino radicals.

2. The method of p'roducinga basic ester of the formula wherein X, X, Y and Y are members of the group consisting of hydrogen, lower alkyl and lower alkoxyl radicals, R is a lower alkylene radical, and B is an amino radical selected from the group consisting of di(lower alkyl) amino, N-piperidino, N-morpholino and N-pyrrolidino radicals, which comprises reacting an aminoalkyl halide of the formula B-R-halogen with an acid of the formula in an inert organic solvent and isolating the basic ester formed.

3. The method of producing a di(lower alkyl) amino-lower-alkyl anthranilate wherein the nitrogen atom 01' the anthranilic acid bears two monocyclic aromatic hydrocarbon substituents, which comprises reacting a di(lower alkyD- amino-lower-alkyl halide with an anthranilic acid bearing two monocyclic aromatic hydrocarbon substituents on the nitrogen atom thereof.

4. The method of producing a di(lower alkyl) amino lower alkyl diphenylanthranilate which comprises reacting a di(lower alkyl) aminolower-alkyl halide, wherein the alkyl groups contain not more than carbon atoms. with N ,N-diphenylanthranilic acid, in an inert organic solvent'and isolating the basic ester formed.

5. The method of producing a diethylaminoethyl N,N-diphenylanthranilate which'comprises reacting a diethylaminoethyl halide with N,N-diphenylanthranilic acid, in an inert organic solvent and isolating the basic ester formed.

.6. A salt of a di (lower alkyl) amino-lower-alkyl anthranilate wherein the nitrogen atom of the anthranilic acid nucleus bears two monocyclic aromatic hydrocarbon substituents.

7. A salt of a di(lower alkyl) amino-lower-alkyl N,N-diphenylanthranilate.

8. A salt of a p-diflower alkyl) aminoethyl N,N-diphenylanthranilate.

9. A salt of ,B-diethylaminoethylN,N-dipheny1- anthranilate.

10. p-Diethylaminoethyl N,N-diphenylanthranilate hydrochloride.

11. A salt of a basic ester of the formula Wherein Ar and Ar are monocyclic aromatic hydrocarbon radicals, R is a lower alkylene radical and Z is a lower alkylene radical.

12. A salt of a basic ester defined as in claim 11 wherein Ar and Ar are phenyl radicals.

13. A salt of a basic ester defined as in claim 11 wherein Ar and Ar are phenyl radicals and R is an ethylene radical. 14. A salt of ,B-N-piperidinoethyl N,N-diphen+ ylanthranilate.

15. p-N-Piperidinoethyl N,N-diphenylanthranilate hydrochloride.

CARL PETER KRIIVIMEL.

REFERENCES CITED.

The following references are or record in the file of this patent:

UNITED STATES PATENTS OTHER REFERENCES Goldberg et al., Ber. Deut. Chem., vol. 40, pp. 2448-2452 (1907). 

1. A MEMBER OF THE GROUP CONSISTING OF A BASIC ESTER OF THE FORMULA 